# TFAP2A

## Overview
TFAP2A is a gene that encodes the transcription factor AP-2 alpha, a sequence-specific DNA-binding protein that plays a pivotal role in regulating gene expression during embryonic development and cell differentiation. As a member of the AP-2 family of transcription factors, AP-2 alpha is characterized by its helix-span-helix (HSH) domain, which facilitates dimerization, and a DNA-binding domain (DBD) that enables interaction with specific DNA sequences (Liu2023Structural). The protein is involved in various cellular processes, including cell growth, apoptosis, and differentiation, and is particularly crucial for neural crest development, impacting craniofacial, limb, and skin formation (Eckert2005TheAP2familyoftranscriptionfactors; Williams1991Analysis). TFAP2A's function is modulated by interactions with other proteins and post-translational modifications, such as phosphorylation and sumoylation, which influence its activity in different signaling pathways, including TGF-β signaling (Koinuma2009Chromatin; Eckert2005TheAP2familyoftranscriptionfactors). Mutations in TFAP2A are linked to several clinical conditions, including branchio-oculo-facial syndrome and various ocular phenotypes, underscoring its significance in human development and disease (Li2013Analysis; Gestri2009Reduced).

## Structure
The TFAP2A protein, encoded by the TFAP2A gene, is a transcription factor characterized by a DNA-binding domain (DBD) and a helix-span-helix (HSH) domain. The DBD spans amino acids 202-273 and consists of two short antiparallel β-strands followed by three α-helices, forming a positively charged binding groove that interacts with DNA (Liu2023Structural). The HSH domain, covering amino acids 293-422, features a flat amphipathic α-helical fold composed of α-helices α4-α8 and is crucial for dimerization, forming homodimers through hydrophobic interactions (Liu2023Structural). The TFAP2A protein can form both homodimers and heterodimers, which is essential for its DNA-binding specificity (Liu2023Structural).

The TFAP2A gene produces multiple isoforms through alternative splicing, with isoforms 1a, 1b, and 1c being the most studied. These isoforms differ in their N-terminal sequences, affecting their biological functions and transactivation activities (Berlato2011Alternative). Isoform 1a is known for its repressive activity, which is linked to a sumoylation site at lysine 10, a post-translational modification that influences its function (Berlato2011Alternative).

## Function
TFAP2A, also known as transcription factor AP-2 alpha, is a sequence-specific DNA-binding protein that plays a crucial role in regulating gene expression during embryonic development and cell differentiation. It is primarily active in the nucleus, where it influences the transcription of genes involved in cell growth, apoptosis, and differentiation (Eckert2005TheAP2familyoftranscriptionfactors; Williams1991Analysis). TFAP2A binds to G/C-rich elements in DNA, utilizing a helix-span-helix motif and a central basic region for dimerization and DNA binding (Eckert2005TheAP2familyoftranscriptionfactors).

In the context of TGF-β signaling, TFAP2A interacts with Smad2/3 and other transcription factors, modulating gene expression in response to signaling pathways. It is involved in both enhancing and inhibiting TGF-β-induced transcriptional activity, depending on the cellular context (Koinuma2009Chromatin). TFAP2A also acts as a co-regulator with TP63 in epidermal differentiation, where it is enriched in TP63-binding sites and plays a role in the regulation of genes associated with skin development (McDade2012Genomewide).

TFAP2A is essential for neural crest development, impacting craniofacial, limb, and skin formation, and is regulated by retinoic acid (Williams1991Analysis). Its activity is modulated by interactions with other proteins and post-translational modifications, such as phosphorylation and sumoylation (Eckert2005TheAP2familyoftranscriptionfactors).

## Clinical Significance
Mutations in the TFAP2A gene are associated with branchio-oculo-facial syndrome (BOFS), an autosomal-dominant condition characterized by craniofacial abnormalities, eye defects, and branchial skin anomalies. These mutations often occur in the DNA-binding domain of the AP-2α protein, leading to altered protein function and dominant-negative effects, which inhibit the function of the wild-type protein. This results in a range of phenotypic variability, including facial clefting, malformed nasal tips, hypertelorism, microphthalmia, and coloboma (Li2013Analysis; Gestri2009Reduced).

In lung adenocarcinoma (LUAD), TFAP2A is implicated in cancer progression through a signaling pathway involving the miR-16 family, PSG9, and TGF-β. Elevated expression of TFAP2A in LUAD is associated with poorer overall survival and progression-free survival, acting as an independent risk factor. The miR-16 family, which targets TFAP2A, is often suppressed in LUAD, leading to increased TFAP2A levels and promoting metastasis through epithelial-mesenchymal transition (Xiong2021TFAP2A).

TFAP2A mutations also contribute to various ocular phenotypes, such as anophthalmia, microphthalmia, and coloboma, by affecting eye development. These mutations can sensitize the eye to defects from other genetic mutations, highlighting TFAP2A's role in eye morphogenesis (Gestri2009Reduced).

## Interactions
TFAP2A, or transcription factor AP-2 alpha, engages in several critical interactions with other proteins and nucleic acids, playing a significant role in transcriptional regulation. It interacts with the co-activators p300 and CBP, which are essential for its transcriptional activation. This interaction is facilitated by CITED2, which binds to the CH1 domain of p300, enhancing the transcriptional activity of TFAP2A. The presence of CITED2 is necessary for the physical interaction between TFAP2A and p300, and the N-terminal residues of TFAP2A are crucial for this interaction (Bragança2003Physical).

TFAP2A also binds to specific DNA sequences, such as those in the CDKN1A promoter, to regulate gene expression. It can activate the CDKN1A promoter independently of p53, binding to specific AP-2 binding sites within the promoter region (Scibetta2010Dual). In the context of epidermal differentiation, TFAP2A acts as a co-factor for TP63, with significant enrichment of AP-2 sites within TP63-binding regions, suggesting cooperative regulation of target genes (McDade2012Genomewide).

These interactions highlight TFAP2A's role in various cellular processes, including development and cancer progression, by modulating gene expression through its interactions with other proteins and DNA.


## References


[1. (Liu2023Structural) Ke Liu, Yuqing Xiao, Linyao Gan, Weifang Li, Jin Zhang, and Jinrong Min. Structural basis for specific dna sequence motif recognition by the tfap2 transcription factors. Nucleic Acids Research, 51(15):8270–8282, July 2023. URL: http://dx.doi.org/10.1093/nar/gkad583, doi:10.1093/nar/gkad583. This article has 5 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/nar/gkad583)

[2. (Berlato2011Alternative) Chiara Berlato, KaYi V Chan, Anna M Price, Monica Canosa, Angelo G Scibetta, and Helen C Hurst. Alternative tfap2a isoforms have distinct activities in breast cancer. Breast Cancer Research, March 2011. URL: http://dx.doi.org/10.1186/bcr2838, doi:10.1186/bcr2838. This article has 18 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1186/bcr2838)

[3. (Li2013Analysis) Hong Li, Ryan Sheridan, and Trevor Williams. Analysis of tfap2a mutations in branchio-oculo-facial syndrome indicates functional complexity within the ap-2α dna-binding domain. Human Molecular Genetics, 22(16):3195–3206, April 2013. URL: http://dx.doi.org/10.1093/hmg/ddt173, doi:10.1093/hmg/ddt173. This article has 32 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1093/hmg/ddt173)

[4. (McDade2012Genomewide) Simon S. McDade, Alexandra E. Henry, Geraldine P. Pivato, Iwanka Kozarewa, Constantinos Mitsopoulos, Kerry Fenwick, Ioannis Assiotis, Jarle Hakas, Marketa Zvelebil, Nicholas Orr, Christopher J. Lord, Daksha Patel, Alan Ashworth, and Dennis J. McCance. Genome-wide analysis of p63 binding sites identifies ap-2 factors as co-regulators of epidermal differentiation. Nucleic Acids Research, 40(15):7190–7206, May 2012. URL: http://dx.doi.org/10.1093/nar/gks389, doi:10.1093/nar/gks389. This article has 80 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/nar/gks389)

[5. (Koinuma2009Chromatin) Daizo Koinuma, Shuichi Tsutsumi, Naoko Kamimura, Hirokazu Taniguchi, Keiji Miyazawa, Makoto Sunamura, Takeshi Imamura, Kohei Miyazono, and Hiroyuki Aburatani. Chromatin immunoprecipitation on microarray analysis of smad2/3 binding sites reveals roles of ets1 and tfap2a in transforming growth factor β signaling. Molecular and Cellular Biology, 29(1):172–186, January 2009. URL: http://dx.doi.org/10.1128/MCB.01038-08, doi:10.1128/mcb.01038-08. This article has 227 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/MCB.01038-08)

[6. (Eckert2005TheAP2familyoftranscriptionfactors) Dawid Eckert, Sandra Buhl, Susanne Weber, Richard Jäger, and Hubert Schorle. The ap-2 family of transcription factors. Genome Biology, 6(13):246, 2005. URL: http://dx.doi.org/10.1186/gb-2005-6-13-246, doi:10.1186/gb-2005-6-13-246. This article has 507 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1186/gb-2005-6-13-246)

[7. (Williams1991Analysis) T Williams and R Tjian. Analysis of the dna-binding and activation properties of the human transcription factor ap-2. Genes & Development, 5(4):670–682, April 1991. URL: http://dx.doi.org/10.1101/gad.5.4.670, doi:10.1101/gad.5.4.670. This article has 386 citations.](https://doi.org/10.1101/gad.5.4.670)

[8. (Gestri2009Reduced) Gaia Gestri, Robert J. Osborne, Alexander W. Wyatt, Dianne Gerrelli, Susan Gribble, Helen Stewart, Alan Fryer, David J. Bunyan, Katrina Prescott, J. Richard O. Collin, Tomas Fitzgerald, David Robinson, Nigel P. Carter, Stephen W. Wilson, and Nicola K. Ragge. Reduced tfap2a function causes variable optic fissure closure and retinal defects and sensitizes eye development to mutations in other morphogenetic regulators. Human Genetics, 126(6):791–803, August 2009. URL: http://dx.doi.org/10.1007/s00439-009-0730-x, doi:10.1007/s00439-009-0730-x. This article has 62 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s00439-009-0730-x)

[9. (Xiong2021TFAP2A) Yanlu Xiong, Yangbo Feng, Jinbo Zhao, Jie Lei, Tianyun Qiao, Yongsheng Zhou, Qiang Lu, Tao Jiang, Lintao Jia, and Yong Han. Tfap2a potentiates lung adenocarcinoma metastasis by a novel mir-16 family/tfap2a/psg9/tgf-β signaling pathway. Cell Death & Disease, April 2021. URL: http://dx.doi.org/10.1038/s41419-021-03606-x, doi:10.1038/s41419-021-03606-x. This article has 38 citations.](https://doi.org/10.1038/s41419-021-03606-x)

[10. (Bragança2003Physical) José Bragança, Jyrki J. Eloranta, Simon D. Bamforth, J. Claire Ibbitt, Helen C. Hurst, and Shoumo Bhattacharya. Physical and functional interactions among ap-2 transcription factors, p300/creb-binding protein, and cited2. Journal of Biological Chemistry, 278(18):16021–16029, May 2003. URL: http://dx.doi.org/10.1074/JBC.M208144200, doi:10.1074/jbc.m208144200. This article has 197 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/JBC.M208144200)

[11. (Scibetta2010Dual) Angelo G. Scibetta, Ping-Pui Wong, KaYi V. Chan, Monica Canosa, and Helen C. Hurst. Dual association by tfap2a during activation of the p21cip/cdkn1a promoter. Cell Cycle, 9(22):4525–4532, November 2010. URL: http://dx.doi.org/10.4161/cc.9.22.13746, doi:10.4161/cc.9.22.13746. This article has 17 citations and is from a peer-reviewed journal.](https://doi.org/10.4161/cc.9.22.13746)